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A Prize-Winning Question

The lab of former Fox Chase investigator Irwin A. “Ernie” Rose (front center) in the late 1970s. Avram Hershko stands in the back row, third from left. Photo by: Fox Chase Archives

In studying protein death, Fox Chase researchers breathed new life into cancer drugs

When Israeli biochemist Avram Hershko and his then-graduate student Aaron Ciechanover arrived at Fox Chase in the summer of 1979, the institution was already regarded as a top place for cancer research.

“Fox Chase had five members of the National Academy of Sciences, including a Nobel Laureate, which was remarkable for a relatively small research institution,” says Hershko, who found the talented roster of researchers inspiring. He and Ciechanover joined the lab of Fox Chase investigator Irwin A. “Ernie” Rose, where they examined how cells dispose of damaged proteins. Their work laid the foundation for a new class of effective cancer drugs and eventually added Hershko, Ciechanover, and Rose to the ranks of Nobel Prize winners.

During the late 1970s, many scientists were researching how proteins are made within cells. Hershko took a different approach. He began to study the other end of the protein’s life cycle—degradation, the process through which cells mark proteins for destruction, then destroy and dispose of them.

Hershko did not know of anyone else who shared this research interest until he met Rose at a scientific conference at the National Institutes of Health. Much to his surprise, Rose, an expert on enzyme mechanisms, had also been looking into protein degradation. Hershko had been scouting for an appropriate location to spend a sabbatical year, and it seemed he had found the perfect match. He asked to join Rose’s lab, and Rose obliged.

“It is my opinion that this is another of the ‘rare events’ in the history of ICR science.”

Continuing his work on protein degradation at Fox Chase, Hershko, together with Rose and his lab, uncovered the role of a molecule called ubiquitin, which cells use to tag proteins that are defective or no longer needed. Special enzymes attach ubiquitin to these obsolete proteins, flagging them for destruction by the proteasome, the cell’s protein garbage disposal. “I remember the moment of great excitement when the results of the experiment came out from the film-developing machine showing that ubiquitin targets proteins for degradation,” says Hershko. Ubiquitin became known as the molecular “kiss of death.”

In decoding this process, Hershko, Rose, Ciechanover, and their colleagues helped future researchers understand how cancers develop when the degradation cycle is disrupted. “The implications are enormous,” wrote Alfred Knudson Jr. in 1979 as then-director of the Institute for Cancer Research, the early name for Fox Chase’s scientific enterprise. “It is my opinion that this is another of the ‘rare events’ in the history of ICR science.”

The implications of the discovery weren’t fully realized until 2003, when a drug came to market that harnessed the power of ubiquitin. Bortezomib, known commercially as Velcade, interferes with the proteasome to help destroy tumors in multiple myeloma, a cancer of the bone marrow. It was the first medication based on the Fox Chase team’s research to be approved by the FDA.

In 2004, Hershko, Ciechanover, and Rose were awarded the Nobel Prize in Chemistry for their work. “It does not mean that a miracle drug to beat cancer is on the way,” said Hershko in an interview with the Associated Press in 2004. “But I do believe there will be advances in the treatment of cancer based on our work. This I truly believe in.” Since Velcade, several cancer treatment medications based on this research have come to market.

Since the profound success of his first sabbatical at Fox Chase, Hershko has returned several times over the following decades to continue his research on ubiquitin. Together with Fox Chase biochemist Timothy J. Yen, he is currently studying how ubiquitin works in mitosis, the process of cell division. “Someone who has uncontrolled mitosis will have tumors,” explains Yen. “Until we understand how a cell regulates cell division correctly, we won’t understand how it does it incorrectly, as in the case of cancer.”

With 35 years and a Nobel Prize behind him, Hershko, now 76, remains as dedicated to his research as ever. “It takes a lot of hard work, determination, and patience to find the answer to the question,” he says. Yen seconds that, citing Hershko’s earlier achievements. “Great discoveries don’t come by design. They come from asking good questions.”

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